The respiratory syncytial virus (RSV) is the most common cause of viral lower respiratory tract infections in infants and children, affecting about 4 million children globally and leading to about 100,000 hospitalizations and 4,500 deaths per annum in the United States alone. RSV infection is associated with recurrent episodes of bronchiolitis, bronchial obstruction and exacerbation of asthma in children. Incidence of RSV infection-induced bronchiolitis has been increasing. There is no effective prophylaxis available against RSV infection. Previous attempts to develop a vaccine using a formalin-inactivated RSV vaccine not only failed but also exacerbated the disease when subsequent RSV infection occurred. (Chanock et al, Serious respiratory tract disease caused by respiratory syncytial virus: prospects for improved therapy and immunization, Pediatrics 1992; 90:137–43). Further, development of therapy against RSV has been limited by the short incubation period. Thus, development of an RSV vaccine has been a high priority at a global level.
Most of the RSV antigens are immunogenic in humans and mice, although the F and G antigens induce the majority of the neutralizing antibodies against RSV. (Connors, et al, Respiratory syncytial virus (RSV) F, G, M2 (22K), and N proteins each induce resistance to RSV challenge, but resistance induced by M2 and N proteins is relatively short-lived, J Virol 65.1634,1991; Wyatt et al, Priming and boosting immunity to respiratory syncytial virus by recombinant replication-defective vaccinia virus MVA. Vaccine 18:392, 1999). An analysis of the CTL repertoire in humans indicates that the N, SH, F, M, M2, and NS2 proteins are strong target antigens. Similarly, in BALB/c mice, the F, N, and especially the M2 proteins are shown to be the major target antigens of CTL activity. (Domachowske et al, Respiratory syncytial virus infection: immune response, immunopathogenesis, and treatment, Clin Microbiol Rev 12:298, 1999). Virus specific cytotoxic T lymphocytes play a major role in the clearance of RSV infection. Both serum and mucosal antibodies and MHC-class-I restricted cytotoxic T lymphocytes (CTLs) mediate protection against RSV infection. (Brandenburg et al, Pathogenesis of RSV lower respiratory tract infection: implications for vaccine development. Vaccine 19:2769, 2001). Previously, passive administration of neutralizing serum antibodies was shown to decrease the risk of RSV disease in animal models and in humans. (Groothuis et al, Use of intravenous gamma globulin to passively immunize high-risk children against respiratory syncytial virus: safety and pharmacokinetics. The RSVIG Study Group. Antimicrob Agents Chemother. 1991 July; 35(7): 1469–73; Hemming et al, Hyperimmune globulins in prevention and treatment of respiratory syncytial virus infections. Clin Microbiol Rev. 1995 January; 8(1):22–33. Review).
Vaccines studied to date comprise a subunit, peptide, or DNA vaccine made up of the RSV-F, -G and/or -M2 protein(s). Intramuscular injection of pDNA encoding the RSV-F or -G protein was effective in mice. (Li et al, Protection against respiratory syncytial virus infection by DNA immunization, J Exp Med 1998 Aug. 17; 188(4):681–8; Li et al, Plasmid DNA encoding the respiratory syncytial virus G protein is a promising vaccine candidate, Virology. 2000 Mar. 30; 269(1): 54–65). In a cotton rat model, an F-G vaccine induced neutralizing antibody titers, which are 1–2 orders of magnitude lower compared to live RSV. (Prince et al, Efficacy and safety studies of a recombinant chimeric respiratory syncytial virus FG glycoprotein vaccine in cotton rats. J Virol. 2000 November;74(22): 10287–92). Immunization with plasmid DNAs (pDNA) expressing antigens in vivo that induce a protective cellular and humoral immune response is touted to have a number of advantages compared to other vaccines. However, the quantity of DNA used per unit bodymass and the route chosen might make these vaccines unsuitable for human use. (Guy et al, Design, characterization and preclinical efficacy of a cationic lipid adjuvant for influenza split vaccine, Vaccine 19:1794, 2001).
Currently, one of the options available to infants, who are at a high risk for developing RSV infection, is passive immunization at a monthly interval with a humanized antibody to the RSV-F antigen. Despite the inconvenience, expense, and partial effectiveness, passive immunization is often considered the only option, as a safe and effective vaccine against RSV is not available.
Therefore, a need remains for a DNA vaccine capable of mounting mucosal immunity against RSV. Given that infants of 2 to 6 months of age are among the most susceptible to RSV infection and that vaccination would preferably take place in the one month old infant, and given that a mucosal vaccine is considered more appropriate for developing a local immunity in these infants, who may have an immature local and systemic immune system, a mucosal RSV vaccine is preferred.